Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCOP(OCC)(C[C:7]#[N:8])=O.[CH3:12][O-].[Na+].O=[C:16]([CH2:18][CH2:19][N:20]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[S:21]1(=[O:23])=[O:22])[CH3:17]>CN(C)C=O>[O:22]=[S:21]1(=[O:23])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=2[C:30](=[O:31])[N:20]1[CH2:19][CH2:18][C:16]([CH3:12])=[CH:17][C:7]#[N:8]
Reactant: C[O-]
Reactant: CC(=O)CCN1C(=O)c2ccccc2S1(=O)=O
Reactant: CCOP(=O)(CC#N)OCC
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=CC#N)CCN1C(=O)c2ccccc2S1(=O)=O
Yield: 20 %

Procedure:
9.5 g (54 millimoles) of diethyl cyanomethyl phosphonate and 8.7 g (48 millimoles) of 30% strength sodium methylate were simultaneously added dropwise to 10.0 g (40 millimoles) of N-(2-oxobut-4-yl)-saccharin in 150 ml of absolute dimethylformamide, while stirring thoroughly. The reaction mixture was stirred for a further 5 hours at 40° C., after which the contents of the flask were poured onto ice-water, and the precipitated crystals were filtered off under suction and recrystallized from ethanol to give 2.2 g (20%) of 4-(2,3-dihydro-1,1-dioxido-3-oxo-1,2-benzisothiazol-2-yl)-1-cyano-2-methylbut-1-ene of melting point 117°-118° C.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH:4]([NH:26][S:27]([C:30]1[C:35]([CH3:36])=[CH:34][C:33]([CH3:37])=[CH:32][C:31]=1[CH3:38])(=[O:29])=[O:28])[CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([C:14](=[O:25])[NH:15][CH2:16][CH2:17][NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:12][CH:13]=1)=[O:8].[OH-].[Li+].C(O)(=O)C>C(#N)C.C(OCC)(=O)C>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[NH:18][CH2:17][CH2:16][NH:15][C:14]([C:11]1[S:10][C:9]([C:7]([NH:6][CH2:5][CH:4]([NH:26][S:27]([C:30]2[C:31]([CH3:38])=[CH:32][C:33]([CH3:37])=[CH:34][C:35]=2[CH3:36])(=[O:29])=[O:28])[C:3]([OH:39])=[O:2])=[O:8])=[CH:13][CH:12]=1)=[O:25]
Reactant: COC(=O)C(CNC(=O)c1ccc(C(=O)NCCNc2ccccn2)s1)NS(=O)(=O)c1c(C)cc(C)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cc(C)c(S(=O)(=O)NC(CNC(=O)c2ccc(C(=O)NCCNc3ccccn3)s2)C(=O)O)c(C)c1
Yield: 86 %

Procedure:
A mixture of 3-({5-[2-(Pyridin-2-ylamino)-ethylcarbamoyl]-thiophene-2-carbonyl}-amino)-2-(2,4,6-trimethyl-benzenesulfonylamino)-propionic acid methyl ester (40 mg, 0.069 mmol), lithium hydroxide (34 mg, 1.39 mmol), in acetonitrile (10 mL) was stirred for 4 hrs at room temperature. The solvent was removed and the crude reaction product was taken up in ethyl acetate (40 mL). The solution was neutralized with acetic acid (1.0 mL). Solvent was than dried over sodium sulfate and evaporated. Purification of the residue on silica gel (10% MeOH-EtOAc) gave 40 mg of pure acetic acid salt of 3-({5-[2-(Pyridin-2-ylamino)-ethylcarbamoyl]-thiophene-2-carbonyl}-amino)-2-(2,4,6-trimethyl-benzenesulfonylamino)-propionic acid (86%). 1HNMR (300 MHz, CD3OD) δ: 2.22 (s, 3H), 2.61 (s, 6H), 3.57 (m, 4H), 3.82 (m, 2H), 6.50(d, 1H), 6.69(m, 2H), 6.90(s, 2H), 7.42(m, 3H), 8.01 (m, 1H). Compound XXXVI: 2-Benzenesulfonylamino-3-({5-[(1H-benzoimidazol-2-ylmethyl)-carbamoyl]-thiophene-2-carbonyl-amino)-propionic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6](Cl)=[CH:7][CH:8]=2)[N:3]=1.Cl.[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17][SH:18].[OH-].[K+].CS(C)=O>C(O)C>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([S:18][CH2:17][CH2:16][N:15]([CH3:19])[CH3:14])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: CN(C)CCS
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: CN(C)CCSc1ccc2ccc(N)nc2n1
Temperature: 90 °C
Yield: 53.8 %

Procedure:
A mixture composed of 2-amino-7-chloro-1,8-naphthyridine (29.6 g), 2-dimethylaminoethanethiol hydrochloride (48 g), potassium hydroxide pellets (85% pure; 43.5 g) and dimethyl sulphoxide (300 cc) is heated for 2 hours at 90° C. The reaction mixture is then poured into distilled water (400 cc) and extracted with methylene chloride (6×250 cc). The extracts are washed with distilled water (300 cc), dried over magnesium sulphate and concentrated to dryness at 40° C. under reduced pressure. The residue obtained is taken up with ethanol (100 cc) and the insoluble product is separated by filtration, washed with ethanol (2×30 cc) and dried at 40° C. under reduced pressure (0.07 kPa). 2-Amino-7-(2-dimethylaminoethylthio)-1,8-naphthyridine (22 g), m.p. 174° C., is obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]2[CH2:15][CH2:16][CH3:17])=O.COC1C=CC(/C=[C:33]2/[C:34]([NH:36][C:37]([S:39]/2)=[NH:38])=[O:35])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:38][C:37]1[S:39]/[C:33](=[CH:1]\[C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]3[CH2:15][CH2:16][CH3:17])/[C:34](=[O:35])[N:36]=1
Reactant: CCCc1c(C#N)cnc2ccc(C=O)cc12
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCc1c(C#N)cnc2ccc(/C=C3\SC(N)=NC3=O)cc12

Procedure:
Similar procedure as described in example 28c was used, starting from 6-formyl-4-propyl-quinoline-3-carbonitrile (example 71c), pseudothiohydantoin, sodium acetate and acetic acid to give 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-propyl-quinoline-3-carbonitrile. LC-MS m/e 323 (MH+).
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][N:4]=1)#[N:2].[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)(N)[C@@H:22]([NH2:28])[CH2:23][O:24][CH2:25][O:26][CH3:27])=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.FC(F)(F)S([O-])(=O)=O.[Sc+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[CH2:12]([O:11][C:9]([C:7]1[CH:6]=[CH:5][N:4]=[C:3]([C:1]2[NH:28][C@@H:22]([CH2:23][O:24][CH2:25][O:26][CH3:27])[C:21]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)([C:18]3[CH:17]=[CH:16][C:15]([F:14])=[CH:20][CH:19]=3)[N:2]=2)[N:8]=1)=[O:10])[CH3:13]
Reactant: COCOC[C@H](N)C(N)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CCOC(=O)c1ccnc(C#N)n1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccnc(C2=NC(c3ccc(F)cc3)(c3ccc(F)cc3)[C@H](COCOC)N2)n1
Temperature: 110 °C
Reaction time: 4 h
Yield: 61.4 %

Procedure:
2-Cyano-4-ethoxycarbonylpyrimidine (207.3 mg) and scandium trifluoromethanesulfonate (48.8 mg) were added to a solution of (2R)-1,1-bis(4-fluorophenyl)-3-methoxymethoxy-1,2-propanediamine (303.5 mg) in toluene (2.0 mL), and the mixture was stirred at 110° C. for 4 hours. The reaction mixture was concentrated in vacuo, and then the residue was purified by silica gel column chromatography (C-300; hexane: ethyl acetate=1:1Δ1:2) to give (5R)-2-(4-ethoxycarbonyl-2-pyrimidyl)-4,4-bis(4-fluorophenyl)-5-[(methoxymethoxy)methyl]-2-imidazoline (279 mg). The obtained ester compound was dissolved in methanol (2 mL), and ammonia gas was passed through the solution at −78° C. for 20 minutes. Then the solution was stirred at room temperature for 20 hours. The reaction mixture was concentrated in vacuo, and then the residue was purified by silica gel column chromatography (C-300; hexane: ethyl acetate=1:1→chloroform: methanol=9:1) to give the corresponding amide compound (273 mg). Triethylamine (0.75 mL) and trifluoroacetic anhydride (0.26 mL) were added at −78° C. to a solution of the obtained amide compound in tetrahydrofuran (2 mL), and the temperature of the mixture was raised up to room temperature, followed by stirring for 7 hours. Water was added to the reaction mixture, and the mixture was extracted by ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then sodium sulfate was removed by filtration. Then the organic solvent was evaporated in vacuc. The residue was purified by silica gel column chromatography (C-300; hexane: ethyl acetate=1:1→1:2) to give the corresponding cyano compound (178 mg). The obtained cyano compound was dissolved in tetrahydrofuran (6 mL), and 6N hydrochloric acid (6 mL) was added to the solution. Then the mixture was stirred at room temperature for 5 hours. Saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture carefully, and the mixture was extracted by ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then sodium sulfate was removed by filtration. The organic solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (C-300; chloroform: ethyl acetate=2:1) to give the title compound (74.7 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][CH:7]([N:18]([CH2:23][C:24]([OH:26])=[O:25])[CH2:19][C:20]([OH:22])=[O:21])[CH2:8][N:9]([CH2:14][C:15]([OH:17])=[O:16])[CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[C:34](Cl)(Cl)=[S:35].C1C=CC(C2C(=O)C3(OC(=O)C4C3=CC=CC=4)OC=2)=CC=1>O.C(Cl)(Cl)Cl>[N:1]([C:2]1[CH:28]=[CH:27][C:5]([CH2:6][CH:7]([N:18]([CH2:19][C:20]([OH:22])=[O:21])[CH2:23][C:24]([OH:26])=[O:25])[CH2:8][N:9]([CH2:10][C:11]([OH:13])=[O:12])[CH2:14][C:15]([OH:17])=[O:16])=[CH:4][CH:3]=1)=[C:34]=[S:35]
Reactant: Nc1ccc(CC(CN(CC(=O)O)CC(=O)O)N(CC(=O)O)CC(=O)O)cc1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: O=C1OC2(OC=C(c3ccccc3)C2=O)c2ccccc21
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(O)CN(CC(=O)O)CC(Cc1ccc(N=C=S)cc1)N(CC(=O)O)CC(=O)O

Procedure:
The precursor 5 (0.33 mmol) was taken up in H2O (10 ml) and stirred rapidly in a 10 ml round bottom flask fitted with an addition funnel. The pH was adjusted to 8.5 with solid NaHCO3 and thiophosgene (42 mg, 0.365 mmol) in CHCl3 (10 ml) was added dropwise. Stirring was continued until the solution tested negative for amine by the fluorescamine method. The aqueous layer was taken to dryness. Purification was done by column chromatography on a 1×30 cm Florisil™ column eluted with acetonitrile:water (30:8). The product eluted from the column cleanly as determined by TLC and was stored in a dessicator in a freezer and re-purified immediately prior to use.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][C:16]1[O:20][C:19]([CH2:21][NH2:22])=[CH:18][CH:17]=1.N[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:15][C:16]1[O:20][C:19]([CH2:21][NH:22][C:8]2[CH:7]=[CH:6][C:5]3[C:4]([NH:1][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=2)=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: Cc1ccc(CN)o1
Reactant: Nc1ccccc1
Product: Cc1ccc(CNc2ccc3c(Nc4ccccc4)cccc3n2)o1

Procedure:
The title compound, MS: m/e=330.4 (M+H+), was prepared from 5-nitro-2-chloroquinoline, 5-methyl-2-furanmethanamine and aniline as described in example 26.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]([CH3:14])[CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[Br:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>CCOC(C)=O>[ClH:1].[Br:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N:12]([CH3:14])[CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:22]=[CH:23][CH:24]=1
Reactant: Nc1cccc(Br)c1
Reactant: CN(C)c1ccc2ncc(C#N)c(Cl)c2c1
Solvent: CCOC(C)=O
Product: CN(C)c1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Product: Cl

Procedure:
Prepared from 0.400 g of 4-chloro-6-dimethylaminoquinoline-3-carbonitrile and 3-bromoaniline in the same manner as EXAMPLE 377. The crude product was boiled twice with EtOAc and dried in vacuo (50° C.). The yield of 4-(3-bromophenylamino)-6-dimethylaminoquinoline-3-carbonitrile hydrochloride was 0.621 g as a brown powder: mass spectrum (electrospray, m/e) M+H 366, 368.9.
Reaction SMILES: [F:1][C:2]1[C:24]([F:25])=[CH:23][C:5]2[N:6]([C:10]3[CH2:11][CH2:12][N:13](CC4C=CC=CC=4)[CH2:14][CH:15]=3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[H][H]>C(O)C.C(O)(=O)C.[Pd]>[F:1][C:2]1[C:24]([F:25])=[CH:23][C:5]2[N:6]([CH:10]3[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: [H][H]
Reactant: O=c1[nH]c2cc(F)c(F)cc2n1C1=CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: O=c1[nH]c2cc(F)c(F)cc2n1C1CCNCC1
Reaction time: 8 h

Procedure:
A solution of 5,6-difluoro-1-[1-(phenylmethyl)-1,2,3,6-tetrahydro-4-pyridinyl]-1,3-dihydro-2H-benzimidazol-2-one (D88) (0.7 mmol, 240 mg) in ethanol (10 mL) and acetic acid (2 mL) was treated under argon with 10% palladium on charcoal (50 mg, ˜0.25 eq wt) and the mixture was stirred overnight under 25-30 PSI, then 8 h under 50 PSI of hydrogen at room temperature. The mixture was concentrated under reduced pressure to give a yellow/orange oil which crystallized with a touch of methanol (from evaporation of the methanol). The residue was dissolved again in 10 mL ethanol and 2 mL of acetic acid, then 50 mg of palladium on charcoal was added again under argon and the mixture was stirred under 50 PSI of hydrogen for 9 days, until completion of the reaction. The mixture was concentrated under reduced pressure to give the title compound as the acetate salt. M+H 254.2, M−H 252.2
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].N1C=CC=CC=1.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:17](=[O:18])[O:19][CH2:20][CH3:21])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: CCOC(=O)Cl
Reactant: Cc1ccc(N)cc1Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Nc1ccc(C)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Using a method analogous to that disclosed in Example 1, Step A, of U.S. Pat. No. 4,552,585, a solution of 10.0 grams (0.071 mole) of 3-chloro-4-methylaniline in 100 mL of chloroform was stirred, and 16.7 grams (0.212 mole) of pyridine was added. Ethyl chloroformate, 9.2 grams (0.085 mole), was then added dropwise during a 20 minute period. During the addition the reaction mixture temperature was held between 25°-30° C. with external cooling. Upon completion of addition the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was washed into a separatory funnel with 50 mL of chloroform, and the solution was washed with two 100 mL portions of water and 100 mL of aqueous 5% hydrochloric acid. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a waxy solid residue. The residue was recrystallized from hexane to yield 12.2 grams of ethyl (3-chloro-4-methylphenyl)carbamate; m.p. 51°-52° C.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)[CH2:2][CH2:3][CH3:4].C(Cl)Cl.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>O>[CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[C:9]=1[S:25]([C:22]1[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=1)(=[O:27])=[O:26])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2ccccc2o1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: ClCCl
Product: CCCCc1oc2ccccc2c1S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4.35 g. (0.025 mol.) of 2-n-butylbenzofuran in 25 ml. of methylene chloride was added a solution of 5.16 g. (0.025 mol.) of 4-methoxybenzenesulfonyl chloride in 50 ml. of methylene chloride. The resulting solution was cooled to 0° and 6.9 g. (0.026 mol.) of stannic chloride was added dropwise. The reaction mixture was stirred for 30 minutes in the cold, for 1.5 hours at ambient temperature, then refluxed for ca. 60 hours. The mixture was poured into 200 ml. of water and stirred for 5 minutes. The layers were separated and the organic phase was extracted three times with water. Sodium hydroxide solution (ca. 1%) was added to the organic layer and it was stirred at ambient temperature for 1 hour. The layers were separated and the organic phase was washed three times with water and once with a saturated sodium chloride solution, dried (MgSO4) and evaporated to dryness to give a residue which was chromatographed on a silica gel "dry column" with 9:1 methylene chloride-ether as eluant to give 2-n-butyl-3-(4-methoxyphenylsulfonyl)benzofuran.
Reaction SMILES: [CH:1](=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:11]([C:14]([CH3:16])=[O:15])([CH3:13])[CH3:12].[ClH:17].C(=O)([O-])[O-].[Na+].[Na+]>>[C:4]1([CH:3]=[CH:2][CH:1]([Cl:17])[C:11]([CH3:13])([CH3:12])[C:14](=[O:15])[CH3:16])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cl
Reactant: O=CC=Cc1ccccc1
Reactant: CC(=O)C(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(=O)C(C)(C)C(Cl)C=Cc1ccccc1
Reaction time: 12 h

Procedure:
20 g (0.15 mol) of cinnamaldehyde and 25.8 g (0.3 mol) of methyl isopropyl ketone are initially introduced, and dry hydrogen chloride is passed in at 10° C. until saturation. The mixture is stirred for 12 hours at 20°-25° C. and poured onto water, and the resulting mixture is neutralized by means of sodium carbonate. The neutralized mixture is extracted with methylene chloride and dried, and the methylene chloride is distilled off. 25.7 g (72.4% of theory) are obtained of 1-phenyl-3-chloro-4,4-dimethyl-1-hexen-5-one which has a melting point of 71° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:26])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:16]=2F)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]([O:31][CH3:32])(=[O:30])[CH2:28][SH:29].C1COCC1.[H-].[Na+]>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2([OH:26])[CH:28]([C:27]([O:31][CH3:32])=[O:30])[S:29][C:16]3[C:17]([C:21]([F:22])([F:24])[F:23])=[CH:18][CH:19]=[CH:20][C:15]2=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CS
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2cccc(C(F)(F)F)c2F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C1Sc2c(C(F)(F)F)cccc2C1(O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 55 °C
Reaction time: 1.67 h
Yield: 56 %

Procedure:
To a room temperature solution of 4-(2-fluoro-3-trifluromethyl-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (9.00 g, 24.0 mmol), methyl thioglycolate (2.40 mL, 26.8 mmol), and anhydrous THF (200 mL) under nitrogen was added NaH (1.15 g of a 60% oil dispersion, 28.7 mmol) in one portion. After the gas evolution ceased, the reaction was stirred at 55° C. After 100 min, the reaction was cooled to room temperature and diluted with ethyl acetate (500 mL). The mixture was washed with water (300 mL) and brine (300 mL) successively, dried over magnesium sulfate, filtered, and the solvent removed to afford a sticky white solid. Trituration with 20% ethyl acetatetheptane afforded 6.20 g (56%) of the desired product as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]([NH2:15])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>ClCCl.O>[C:23]([NH:15][CH:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[CH3:1])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)Cl
Reactant: Cc1ccsc1C(N)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)NC(Cc1ccccc1)c1sccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred two-phase mixture of 10 g (0.047 mol) of α-(3-methyl-2-thienyl)benzeneethanamine and 7.4 g (0.07 mol) of sodium carbonate in 150 ml of dichloromethane and 200 ml of water at 0° C. was added dropwise 7.6g (0.07 mol) of ethyl chloroformate. The resulting mixture was allowed to warm to ambient temperature and stirred vigorously overnight. The layers were separated, aqueous phase extracted with CH2Cl2 (2×50 ml), organic layers were combined and washed with 1N aqueous hydrochloric acid, brine, and dried. The crude N-carbethoxy-α-(3-methyl-2-thienyl)benzeneethanamine thus obtained was purified by silica gel chromatography to give 13.3 g of a pale yellow oil. A solution of 7.5 g (0.026 mol) of the oil in tetrahydrofuran (50 mL) was added dropwise to a stirred solution of 22 ml (0.075 mol) of a 3.4M solution of sodium bis (2-methoxyethoxy)aluminum hydride in toluene (Red-AL) dissolved in 150 ml of tetrahydrofuran at ambient temperature. The mixture was stirred overnight and quenched by dropwise addition of isopropanol until bubbling had ceased followed by dropwise addition of water until a white precipitate formed. After stirring for 30 minutes longer, the clear yellow solution was decanted and concentrated to dryness giving the crude product as an oil. The oil was dissolved in 50 ml of isopropanol, chilled to 0° C., and made acidic with hydrochlorinated isopropanol. The resulting white solid was collected by filtration and freeze-dried from water to give 1.8 g of white solid product (mp 214°-216° C.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([CH3:21])=[N:11][C:12]([O:16][CH2:17][C:18]([OH:20])=O)=[N:13][C:14]=1[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([N:29]1[CH2:34][CH2:33][CH:32]([NH:35][CH3:36])[CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>C(#N)C>[CH2:22]([N:29]1[CH2:34][CH2:33][CH:32]([N:35]([CH3:36])[C:18](=[O:20])[CH2:17][O:16][C:12]2[N:13]=[C:14]([CH3:15])[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[C:10]([CH3:21])[N:11]=2)[CH2:31][CH2:30]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CNC1CCN(Cc2ccccc2)CC1
Reactant: Cc1nc(OCC(=O)O)nc(C)c1NC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nc(OCC(=O)N(C)C2CCN(Cc3ccccc3)CC2)nc(C)c1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 150.7 %

Procedure:
Compound 9 (74.74 g), 1-benzyl-N-methylpiperidine-4-amine (66.78 g: 1.3 eq.) and triethylamine (127.20 g: 5 eq.) were suspended in acetonitrile (800 mL). While the suspension was cooled on ice, a 50% propanephosphonic acid anhydride ethyl acetate solution (191.99 g) was added portionwise. The equipment used to add 50% propanephosphonic acid anhydride ethyl acetate solution was thoroughly washed with acetonitrile (192 mL) and stirred at room temperature (20 to 30° C.) overnight. Subsequently, the mixture was concentrated under reduced pressure. To the resulting residue, chloroform (250 mL) and a saturated aqueous sodium bicarbonate solution (140 mL) were sequentially added and the mixture was transferred to a separation funnel. The reaction container was thoroughly washed with chloroform (175 mL) and separation was performed. Once the organic layer was separated, chloroform (175 mL) was added to the aqueous layer and separation was performed again. The collected organic layer was dried over magnesium sulfate and was suction-filtered. The filtrate was evaporated under reduced pressure to give 183.27 g of the crude desired product of Compound 30 as a yellow amorphous.
Reaction SMILES: C([Mg]Br)C.[Mg].C(Br)C.[CH2:9]([OH:12])[C:10]#[CH:11].Cl[CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C1COCC1>[CH2:9]([OH:12])[C:10]#[C:11][CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCC/C=C\C/C=C\CCl
Reactant: C#CCO
Agent: CC[Mg]Br
Agent: [Mg]
Solvent: CCBr
Solvent: C1CCOC1
Product: CCCCC/C=C\C/C=C\CC#CCO
Temperature: 23 °C
Yield: 98.5 %

Procedure:
A solution off ethylmagnesium bromide in THF (10 ml) was prepared from magnesium (1.4 g, 57.7 mmol) and ethyl bromide (7.7 g, 71 mmol). Propargyl alcohol (1.53 g, 27.4 mmol) in dry THF (6 ml) was then added dropwise to the above ethylmagnesium bromide solution at 5° C. with vigorous stirring. The resulting viscous mixture was stirred at 23° C. under argon for twenty minutes. Cuprous chloride (0.14 g) was added and the reaction mixture was further stirred for twenty minutes. A solution of (Z,Z)-1-chloro-2,5-undecadiene (3.4 g, 18.2 mmol) in THF (2.0 ml) was then added dropwise to the above mentioned mixture over a period of twenty five minutes, at 20° C. The reaction mixture was stirred at 50° C. under argon for 18 h. The THF was removed at ~35° C. on a rotary evaporator and the resulting residue was treated with cold 1.5N H2SO4 (150 ml). It was extracted with ether, washed with water, and dried over Na2SO4. Evaporation of ether at reduced pressure gave 3.7 g of light yellow oil which was chromatographed on 70 g of silica gel. Elution with ether-petroleum ether (1:3) gave 2.3 g (61%) of (Z,Z)-5,8-tetradecadien-2-yl-1-ol which was evaporatively distilled at 137°-140° C./0.3 mm Hg as a colorless liquid.